In humans, recombination plays a critical role in meiosis. Errors in the recombination process lead to aneuploidy, the leading cause of spontaneous miscarriages and of severe developmental disabilities, as well as to deleterious genome rearrangements and possibly to mutations. Yet in spite of its highly constrained roles, recombination is tremendously variable among humans, at every scale examined. Our long-term research interests lie in characterizing this variation, identifying its determinants and understanding its biomedical and evolutionary implications. In particular, our work revealed heritable variation in the set of recombination hotspots used by different individuals, contributing to the discovery of PRDM9 (a gene of central importance in specifying hotspot locations in mice and humans). This case demonstrates how studies of variation in recombination can yield insight into mechanism. We also documented an effect of recombination rates on female fertility, notably in older mothers. Together, our findings and those from other groups underscore the biomedical importance of understanding the determinants of recombination rate variation and their effects. In this competitive renewal, we propose to analyze a huge set of human pedigrees in order to examine the basis for differences in recombination rates among individuals and the consequences for aneuploidy risk and mutagenesis. In Aim 1, we focus on differences between sexes. We propose to build a fine-scale, sex-specific genetic map at unprecedented resolution and characterize sex-specific hotspots, by analyzing over 3000 nuclear families that have already been genotyped. In Aim 2, we will conduct a well-powered genome-wide association study to identify new loci that contribute to variation in recombination phenotypes, using the same set of nuclear families. In Aim 3, we plan to examine how variation in recombination rates and maternal age influence the risk of aneuploidy. In Aim 3.i, we will assess the evidence for proper segregation of tetrads without a crossover, i.e., for the presence of a back-up mechanism for achiasmatic chromosomes. In Aim 3.ii, we will characterize the recombination patterns that endanger proper disjunction. To this end, we will collect and analyze samples from women and their trisomic products of conception, contrasting patterns of recombination in this set to age-matched transmissions to viable, non-trisomic offspring. Finally, in Aim 4, we will test whether recombination introduces germline mutations at non-negligible rates, by collecting and analyzing genome sequences for two large nuclear families. This work will yield important new insights into the determinants of recombination rate variation and the implications for human reproductive health and genome evolution.